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Mrc1 facilitates epigenetic inheritance through proper parental histone segregation

ABSTRACT: Chromatin-based epigenetic memory relies on the equal distribution of parental histone tetramers, which serve as templates for duplicating parental chromatin, to newly synthesized daughter DNA strands. Histone chaperones within the replisome, such as the histone binding domains (HBDs) of Mcm2 and Pol alpha, are critical for transferring parental histones to the lagging strand. However, the mechanisms and impact of parental histone transfer on epigenetic inheritance remain debated. Using fission yeast heterochromatin assembly as a model, we discovered that replisome component Mrc1 is crucial for both epigenetic inheritance and transfer of parental histones to the lagging strand, akin to a Mcm2-HBD mutation. Isolation of separation-of-function mutations revealed that Mrc1’s role in epigenetic inheritance is distinct form its DNA replication checkpoint and replisome speed control functions. Instead, Mrc1 prevents undesirable replisome interactions to facilitate interactions between Mcm2 and Pol alpha for the proper passage of parental histones. These findings unveil a novel function of Mrc1 and underscore the critical role of parental histone segregation in epigenetic inheritance.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE237700 | GEO | 2026/01/01

REPOSITORIES: GEO

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Mrc1 facilitates epigenetic inheritance through proper parental histone segregation

Project description:Chromatin-based epigenetic memory relies on the equal distribution of parental histone tetramers, which serve as templates for duplicating parental chromatin, to newly synthesized daughter DNA strands. Histone chaperones within the replisome, such as the histone binding domains (HBDs) of Mcm2 and Pol alpha, are critical for transferring parental histones to the lagging strand. However, the mechanisms and impact of parental histone transfer on epigenetic inheritance remain debated. Using fission yeast heterochromatin assembly as a model, we discovered that replisome component Mrc1 is crucial for both epigenetic inheritance and transfer of parental histones to the lagging strand, akin to a Mcm2-HBD mutation. Isolation of separation-of-function mutations revealed that Mrc1s role in epigenetic inheritance is distinct form its DNA replication checkpoint and replisome speed control functions. Instead, Mrc1 prevents undesirable replisome interactions to facilitate interactions between Mcm2 and Pol alpha for the proper passage of parental histones. These findings unveil a novel function of Mrc1 and underscore the critical role of parental histone segregation in epigenetic inheritance.

2023-07-16 | MSV000092452 | MassIVE

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Project description:Chromatin replication is intricately intertwined with DNA replication, and the recycling of parental histones is essential for epigenetic inheritance. The transfer of parental histones to both the DNA replication leading and lagging strands involves two distinct pathways: the leading strand utilizes DNA polymerase ε subunits Dpb3/Dpb4, while the lagging strand is facilitated by the MCM helicase subunit Mcm2. However, the process by which Mcm2, moving along the leading strand, facilitates the transfer of parental histones to the lagging strand remains unclear. Our study reveals that the deletion of Pol32, a non-essential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the replication leading strand. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted by the mutation of Mcm2's histone H3-H4 binding domain. In conclusion, our findings identify the DNA polymerase delta subunit Pol32 as a novel key histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

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Project description:During DNA replication parental, nucleosomic histones are segregated almost symmetrically to the two daughter DNA strands enabling mitotic inheritance of histones and their PTMs. In MCM2 histone-binding mutant ESCs (MCM2-2A), histones are recycled asymmetrically to the leading strand. To evaluate if loss of parental histones contributes to the asymmetry, we tracked new and old histones quantitatively by pulse-Triple-SILAC-MS. The quantification showed no change in dilution and incorporation dynamics in MCM2-2A cells, demonstrating that parental histones are not lost at replication forks but re-routed from the lagging to the leading strand.

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The Mcm2-Ctf4-Pola axis facilitates parental histone transfer to lagging strands

Project description:Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Pol axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging strands of DNA replication forks. Mutating the H3-H4 binding domain of Mcm2, a subunit of the CMG (Cdc45-MCM-GINS) replicative helicase that translocates along leading strands, impairs the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Pol-primase mutants that disrupt the connection of the CMG helicase via Ctf4-Pol to lagging strands. Our results support a model whereby parental (H3-H4)2 displaced from nucleosomes through leading-strand DNA replication are transferred to lagging strands for nucleosome assembly via the CMG-Ctf4-Pol complex.

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